A Randomized, Sham-Controlled, Quintuple-Blinded Trial to Evaluate the Net Device as an alternative to Medication For Promoting Opioid abstinence

BACKGROUND: There is an unmet need for non-medication approaches to illicit opioid discontinuation and relapse prevention. The NET (NeuroElectric Therapy) Device is a non-invasive, battery-operated, portable, re-useable device designed to deliver bilateral transcranial transcutaneous alternating current electrical stimulation, and is intended to treat opioid use disorder (OUD) without medication. The device is a CE-marked Class IIa, non-significant risk, investigational medical device. OBJECTIVE: This prospective trial (NRC021) tests the hypothesis that the NET Device provides safe and effective neurostimulation treatment for persons with OUD who express a desire to be opioid abstinent without medications for opioid use disorder (MOUD). METHODS: NRC021 is a randomized, parallel-group, sham-controlled, quintuple-blinded, single-site study. Persons with OUD entering a residential treatment facility for opioid detoxification are assigned to active or sham treatment (n = 50/group). Group assignment is stratified on presence of any current non-opioid substance use disorder and by sex. The biostatistician maintains the blinding so that the study sponsor, principal investigator, research assistants, treatment staff, and participants remain blinded. Following discharge from the inpatient facility, participants are assessed once weekly over 12 weeks for substance use (using timeline followback interview and video assessment of observed oral fluid sample provision and testing). The primary efficacy endpoint is each participant\u27s overall percentage of weekly abstinence from illicit opioid use without use of MOUD. The secondary efficacy endpoint is each participant\u27s percentage of non-opioid drug-free weeks. Safety outcomes are also measured. CONCLUSION: NRC021 is designed to assess the efficacy of a novel non-medication treatment for OUD. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov with the identifier NCT04916600

At the intersection of sleep deficiency and opioid use: mechanisms and therapeutic opportunities

Due to the ongoing opioid epidemic, innovative scientific perspectives and approaches are urgently needed to reduce the unprecedented personal and societal burdens of nonmedical and recreational opioid use. One promising opportunity is to focus on the relationship between sleep deficiency and opioid use. In this review, we examine empirical evidence: (1) at the interface of sleep deficiency and opioid use, including hypothesized bidirectional associations between sleep efficiency and opioid abstinence; (2) as to whether normalization of sleep deficiency might directly or indirectly improve opioid abstinence (and vice versa); and (3) regarding mechanisms that could link improvements in sleep to opioid abstinence. Based on available data, we identify candidate sleep-restorative therapeutic approaches that should be examined in rigorous clinical trials

BDNF Val 66 Met genotype is associated with drug‐seeking phenotypes in heroin‐dependent individuals: a pilot study

Brain‐derived neurotrophic factor (BDNF) Val 66 Met genotype has been associated with neurobehavioral deficits. To examine its relevance for addiction, we examined BDNF genotype differences in drug‐seeking behavior. Heroin‐dependent volunteers ( n  = 128) completed an interview that assessed past‐month naturalistic drug‐seeking/use behaviors. In African Americans ( n  = 74), the Met allele was uncommon (carrier frequency 6.8%); thus, analyses focused on European Americans ( n  = 54), in whom the Met allele was common (carrier frequency 37.0%). In their natural setting, Met carriers ( n  = 20) reported more time‐ and cost‐intensive heroin‐seeking and more cigarette use than Val homozygotes ( n  = 34). BDNF Val 66 Met genotype predicted 18.4% of variance in ‘weekly heroin investment’ (purchasing time × amount × frequency). These data suggest that the BDNF Met allele may confer a ‘preferred drug‐invested’ phenotype, resistant to moderating effects of higher drug prices and non‐drug reinforcement. These preliminary hypothesis‐generating findings require replication, but are consistent with pre‐clinical data that demonstrate neurotrophic influence in drug reinforcement. Whether this genotype is relevant to other abused substances besides opioids or nicotine, or treatment response, remains to be determined.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/99593/1/adb431.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/99593/2/adb431_sm_fig_s1.pd

人工心臓への適用を目的としたダブルステータ型磁気浮上ポンプの開発

The clinical pharmacology of fentanyl and alfentanil was examined in opioid-experienced volunteers with agonist and antagonist sensitivity measures. Two studies used within-subject, placebo-controlled, crossover designs. In study 1, fentanyl (0.125, 0.25 mg/70 kg i.v.) was followed at 0, 20, 60 and 180 min by naloxone (10 mg/70 kg i.m.). Agonist effects during 180-min and 0-min (control; simultaneous fentanyl-naloxone i.v. infusion) challenge sessions were compared. Fentanyl rapidly constricted pupils, depressed respiration and produced subjective high and opiate symptoms lasting 60 to 120 min, depending on the measure. Naloxone precipitated withdrawal symptoms of comparable intensity at each challenge point. In study 2, fentanyl (0.125, 0.25 mg/70 kg i.v.), alfentanil (1, 2 mg/70 kg i.v.) and saline were followed at 1 and 6 hr by naloxone (10 mg/70 kg i.m.). Agonist effects were examined during 6-hr challenge sessions. The two drugs produced a comparable range of effects with similar peak magnitude for 0.125 mg/70 kg fentanyl and 1 mg/70 kg alfentanil and for 0.25 mg/70 kg fentanyl and 2 mg/70 kg alfentanil. Alfentanil\u27s duration of action was brief ( \u3c 60 min). Withdrawal was precipitated at 6 hr only after 0.25 mg/70 kg fentanyl. These findings support typical mu opioid characteristics (pleasurable subjective effects, physical dependence) for both drugs, differential duration of action (fentanyl \u3e alfentanil) and peak effects consistent with a 1:8 (fentanyl/alfentanil) potency ratio

Anhedonia modulates benzodiazepine and opioid demand among persons in treatment for opioid use disorder

BACKGROUND: Benzodiazepine (BZD) misuse is a significant public health problem, particularly in conjunction with opioid use, due to increased risks of overdose and death. One putative mechanism underlying BZD misuse is affective dysregulation, via exaggerated negative affect (e.g., anxiety, depression, stress-reactivity) and/or impaired positive affect (anhedonia). Similar to other misused substances, BZD consumption is sensitive to price and individual differences. Although purchase tasks and demand curve analysis can shed light on determinants of substance use, few studies have examined BZD demand, nor factors related to demand. METHODS: This ongoing study is examining simulated economic demand for alprazolam (among BZD lifetime misusers based on self-report and DSM-5 diagnosis; n = 23 total; 14 male, 9 female) and each participant\u27s preferred-opioid/route using hypothetical purchase tasks among patients with opioid use disorder (n = 59 total; 38 male, 21 female) who are not clinically stable, i.e., defined as being early in treatment or in treatment longer but with recent substance use. Aims are to determine whether: (1) BZD misusers differ from never-misusers on preferred-opioid economic demand, affective dysregulation (using questionnaire and performance measures), insomnia/behavioral alertness, psychiatric diagnoses or medications, or urinalysis results; and (2) alprazolam demand among BZD misusers is related to affective dysregulation or other measures. RESULTS: Lifetime BZD misuse is significantly (p \u3c 0.05) related to current major depressive disorder diagnosis, opioid-negative and methadone-negative urinalysis, higher trait anxiety, greater self-reported affective dysregulation, and younger age, but not preferred-opioid demand or insomnia/behavioral alertness. Alprazolam and opioid demand are each significantly positively related to higher anhedonia and, to a lesser extent, depression symptoms but no other measures of negative-affective dysregulation, psychiatric conditions or medications (including opioid agonist therapy or inpatient/outpatient treatment modality), or sleep-related problems. CONCLUSION: Anhedonia (positive-affective deficit) robustly predicted increased BZD and opioid demand; these factors could modulate treatment response. Routine assessment and effective treatment of anhedonia in populations with concurrent opioid and sedative use disorder may improve treatment outcomes

A virtual reality martial arts-based intervention reduces pain, drug craving, and stress in patients with opioid use disorder

Background: Some individuals with opioid use disorder (OUD) report high levels of pain, anxiety, stress and drug craving that may occasion relapse, reduce adherence to treatment, and reduce quality of life. This pilot study evaluated whether a novel martial arts-based intervention can lower self-reported and physiological markers of pain, anxiety, stress and opioid craving in individuals with OUD undergoing methadone maintenance treatment (MMT). Methods: 15 MMT patients (11 females) completed a 12-week ‘Heroes Circle’ intervention that involved twice-weekly 30-min sessions centering around martial arts-based breathing and meditative techniques using therapist-assisted virtual reality (VR). Patients self-reported on five measures (pain, drug craving, anxiety, depression, anger) using a 0-10 scale before (pre) and after (post) each session. Salivary markers of inflammation (C-reactive protein [CRP]) and stress (cortisol) were collected before and after several sessions (baseline, weeks 4, 8, and 12). Results: There were significant pre-post session reductions in rated pain, drug craving, anxiety and depression, and saliva cortisol (ps\u3c0.05). For opioid craving, there was also an effect of week such that craving decreased from weeks 1-6, increased from 7-9, and decreased again from 10-12 (ps\u3c0.05); there was also a session x week interaction such that the pre-post reduction in craving reached significance in weeks 1-3 only. There were no significant main effects or interactions for anger or CRP (ps\u3e0.05). Conclusions: These preliminary results suggest VR-based, martial-arts meditative intervention is a promising approach for reducing pain, anxiety, stress and craving levels among individuals with OUD. Further controlled studies are warranted

Gas-grain simulation facility: Aerosol and particle research in microgravity

This document reports on the proceedings of the Gas-Grain Simulation Facility (GGSF) Science Workshop which was co-hosted by NASA Ames Research Center and Desert Research Institute, University of Nevada System, and held in Las Vegas, Nevada, on May 4-6, 1992. The intent of the workshop was to bring together the science community of potential GGSF experimenters, Science Working Group and staff members, and the Phase A contractor to review the Phase A design with the science participants and to facilitate communication between the science community and the hardware developers. The purpose of this report is to document the information disseminated at the workshop, to record the participants' review of the Phase A GGSF design concept and the current science and technical requirements for the Facility, and to respond to any questions or concerns that were raised at the Workshop. Recommendations for the future based on numerous discussions with the participants are documented, as well as science presentations and poster sessions that were given at the Workshop and a summary of 21 candidate experiments

A novel martial arts-based virtuality reality intervention modulates pain and the pain neuromatrix in patients with opioid use disorder

Background: Standard-of-care for opioid use disorder (OUD) includes medication and counseling. However, there is an unmet need for complementary approaches to treat OUD patients coping with pain; furthermore, few studies have probed neurobiological features of pain or its management during OUD treatment. This preliminary study examines neurobiological and behavioral effects of a martial arts-based intervention in patients undergoing methadone maintenance treatment (MMT). Methods: Fifteen (11 female) MMT patients completed a virtual reality, therapist-guided martial arts intervention that included breathing and relaxation exercises; sessions were scheduled twice weekly. Assessments included functional magnetic resonance imaging (fMRI) of pain neuromatrix activation and connectivity (pre- and post-intervention), saliva cortisol and C-reactive protein (CRP) at baseline and weeks 4, 8 and 12; and self-reported pain and affective symptoms before and after each intervention session. Results: After each intervention session (relative to pre-session), ratings of pain, opioid craving, anxiety and depression (but not anger) decreased. Saliva cortisol (but not CRP) levels decreased from pre- to post-session. From pre- to post-intervention fMRI assessments, pain task-related left postcentral gyrus (PCG) activation decreased. Higher baseline cortisol levels were associated with greater post-intervention pain task-related insular activation. At baseline, PCG showed positive connectivity with other regions of the pain neuromatrix, but this pattern changed post-intervention. Conclusions: These preliminary findings demonstrate feasibility, therapeutic promise, and brain basis of a martial arts-based intervention for OUD patients undergoing MMT